|
|
||||||||
a Department of Cardiothoracic Anesthesia, Cleveland Clinic Foundation, Cleveland, Ohio
b Department of Outcomes Research, Cleveland Clinic Foundation, Cleveland, Ohio
c Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
d Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
e Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio
f Division of Non-Invasive Cardiac Imaging, Mount Sinai Heart, Departments of Medicine and Radiology, Mount Sinai School of Medicine, New York, New York
Accepted for publication February 25, 2008.
* Address correspondence to Dr Duncan, Department of Cardiothoracic Anesthesia, Cleveland Clinic Foundation, 9500 Euclid Ave, G30, Cleveland, OH 44195 (Email: duncana{at}ccf.org).
| Dr Garcia discloses that he has a financial relationship with Phillips, Vital Images, and Pfizer; Dr Gillinov with Edwards Lifesciences, Medtronic, and St. Jude.
|
| Abstract |
|---|
|
|
|---|
Methods: Between January 1996 and June 2004, 5,083 patients underwent aortic valve replacement. Preoperative echocardiographic data was used to calculate LV mass and RWT. Left ventricular geometry was classified into one of four categories on the basis of LV mass indexed to body height and RWT: (1) concentric hypertrophy, (2) eccentric hypertrophy, (3) concentric remodeling, and (4) normal. Postoperative mortality and multisystem morbidities of patients with concentric geometries were compared to patients with nonconcentric geometries by propensity and logistic regression modeling. Also, prognostic ability of RWT and LV mass was compared.
Results: Nine hundred sixty-four patients with concentric geometry were propensity-matched to 964 patients with nonconcentric geometry. In-hospital mortality (38 [3.9%] versus 18 [1.9%]; p = 0.007), cardiac morbidity (33 [3.4%] versus 17 [1.8%]; p = 0.022), and prolonged intubation (85 [8.8%] versus 58 [6.0%]; p = 0.019) were higher in patients with concentric versus nonconcentric geometry. Increasing RWT, not LV mass, was associated with adverse outcomes.
Conclusions: Concentric geometries are associated with increased risk for in-hospital mortality after aortic valve replacement. Increased RWT is associated with adverse outcomes. Preoperative risk stratification should include assessments of LV hypertrophy and LV geometry.
Increases in myocardial mass and alterations in left ventricular geometry (LV) help limit systolic wall stress and preserve ejection fraction in response to ventricular pressure or volume overload. Although limiting wall stress, LV hypertrophy (LVH) is a pathologic condition associated with increasing myocardial connective tissue and fibrosis [1]. Left ventricular geometry may be classified into the following structurally determined categories based on LV mass and relative wall thickness (RWT): (1) concentric hypertrophy, (2) eccentric hypertrophy, (3) concentric remodeling, and (4) normal geometry [2].
The development of LVH in hypertensive patients is associated with adverse long-term outcomes, including myocardial infarction, congestive heart failure, stroke, and death [3]—and may be the most important prognostic indicator of long-term survival [1, 4]. Increased LV mass in uncomplicated hypertensive patients is a reliable predictor for long-term fatal cardiovascular events, independently of arterial pressure, the presence of coronary artery disease, and other risk factors [3–5]. The geometry of the left ventricle further stratifies risk, with concentric LVH heralding poor outcome [1, 3]. Concentric LVH in hypertensive patients is associated with a twofold increase in cardiovascular deaths compared with patients with eccentric hypertrophy [3]. Furthermore, medically treated hypertensive patients with persistent concentric LVH are at highest risk of cardiovascular morbidity and mortality compared with patients with eccentric LVH, even with similar values of LV mass index [6].
Severe LVH is also a risk factor for adverse outcome in surgical patients after aortic valve replacement surgery (AVR), including higher in-hospital mortality [7–9] and more frequent postoperative complications, such as congestive heart failure, low-output syndrome, respiratory failure, renal insufficiency, and atrial and ventricular arrhythmias [8]. Although LV geometry influences outcomes in the nonoperative setting, the influence of type of LV geometry on outcomes in surgical patients remains unclear. Although some reports conclude that concentric LVH in patients with aortic stenosis increases risk for adverse outcome after AVR [7, 10], others reported no difference with wall thickness-to-radius ratio measurements on post-AVR outcomes [11]. Furthermore, eccentric ventricular hypertrophy is thought to increase risk for adverse outcome because of its association with congestive heart failure, ventricular arrhythmias [12], and depressed LV functional response to stress [13]. Thus, the extent to which type of ventricular geometry influences outcomes after AVR remains unclear.
Various measures of LVH severity, including increasing RWT [7, 10], which denotes LV concentric remodeling, and increased LV mass [8, 9], have been used to examine the influence of LVH on outcomes in patients after AVR. Increased RWT was associated with increased mortality in patients undergoing AVR [7, 10], whereas other reports found increased LV mass to predict adverse outcomes [8, 9]. Whether increased LV mass or RWT best identifies increased perioperative risk in patients having AVR has yet to be determined.
Risk stratification of patients who require AVR may be improved by more complete preoperative assessment of LV geometry and identification of which LVH descriptor best predicts adverse outcomes. Furthermore, timing of surgical correction may be improved by attention to specific measures of LVH. We therefore tested the hypothesis that in-hospital mortality after AVR is greater in patients with concentric geometries than in those with nonconcentric geometries. In addition, we compared the ability of RWT versus LV mass to predict increased risk of mortality in patients after AVR.
| Patients and Methods |
|---|
|
|
|---|
Outcome variables as described by Higgins and colleagues [14] included (1) mortality (all-cause in-hospital mortality); (2) cardiac morbidity defined as a combination of postoperative myocardial infarction or low cardiac output with a requirement for intraaortic balloon pump, ventricular assist device, or extracorporeal membrane oxygenation (Postoperative myocardial infarction was defined by specific electrocardiographic findings consistent with myocardial infarction [15] with a creatine phosphokinase myocardial band of at least 50 IU or aspartate aminotransferase level of at least 80 U/L. Low cardiac output was defined as a cardiac index less than 1.8 L · min–1 · m–2 despite adequate fluid replacement and high-dose inotropic agents for more than 4 hours.); (3) neurologic morbidity defined as new postoperative focal deficit (aphasia, decrease in limb function, or hemiparesis confirmed by clinical findings or computed tomographic scan) or global neurologic deficit (diffuse encephalopathy with greater than 24 hours of severely altered mental status, or failure to awaken postoperatively); (4) prolonged intubation defined as a requirement for mechanical ventilation or endotracheal intubation of greater than 72 hours; (5) renal morbidity defined as postoperative anuria or oliguria (urine output less than 400 mL/24 hours) or institution of renal dialysis or ultrafiltration; (6) infection morbidity, including culture-proven pneumonia, mediastinitis, wound infection, or septicemia with appropriate clinical findings; and (7) overall morbidity defined as the incidence of one or more of the above morbidities, including death, since early death precludes observation of morbidity.
Echocardiographic Methods
Echocardiographic indices were obtained from the Adult Echocardiography Laboratory Database at the Cleveland Clinic. Studies were performed using commercially available echocardiographic imaging systems equipped with 3.0- to 3.5-MHz transducers with M-mode, two-dimensional, pulsed, continuous, and color-flow Doppler capabilities. Correct orientation of imaging planes and measurements of LV internal dimension and septal and posterior wall thicknesses were measured at end-diastole, according to the American Society of Echocardiography recommendations [16]. The parasternal long-axis and short-axis views were used to record two-dimensional and M-mode recordings of the LV internal diameter and wall thickness at, or just below, the tips of the mitral leaflets. When optimal perpendicular orientation of the LV M-mode to the ultrasound beam could not be obtained, correctly oriented two-dimensional linear dimensions were made by the American Society of Echocardiography leading-edge convention.
Left ventricular mass was calculated according to the methods described by Devereux and Reichek [17]:
LV mass = 1.04 [(LVID + VST + PWT)3 – (LVID)3] – 13.6 where LVID is left ventricular internal dimension, VST is left ventricular septal thickness, and PWT is left ventricular posterior wall thickness. Left ventricular mass indexed to height (g/m) was used to normalize LV mass measurements according to body size since adjustment by body surface area may not recognize obesity-related hypertrophy. Upper limits of normal for LV mass was defined as 143 g/m for men and 102 g/m for women, corresponding to two standard deviations above the mean values for LV mass in a healthy reference group [2, 18]. Relative wall thickness was calculated as RWT = PWT/ (0.5) LVID, and RWT of 0.45 or less was considered normal.
Left ventricular geometry was classified into one of the following four mutually exclusive groups on the basis of LV geometry: (1) concentric hypertrophy (increased LV mass and increased RWT); (2) eccentric hypertrophy (increased LV mass and normal RWT); (3) concentric remodeling (normal LV mass with increased RWT); and (4) normal geometry (normal LV mass and normal RWT). Standard methods were used to calculate LV ejection fraction [19].
Statistical Methods
The SAS 8.2 software (SAS Institute Inc, Cary, NC) statistical software was used for statistical analysis. Results are expressed as mean ± standard deviation, median (25th, 75th percentiles), and frequencies as percentages. Differences between two groups were assessed by the Student's t test or Wilcoxon rank-sum test for continuous variables and
2 or Fisher's exact test for categorical data as appropriate; analysis of variance was performed for comparison among multiple groups. Transformation was made as needed to meet the linearity assumptions for logistic regression analysis. A probability value of less than 0.05 was used as the significant criterion for each comparison.
Univariate and Propensity Matching
Patients with concentric geometries (concentric hypertrophy and concentric remodeling) were compared with patients with nonconcentric geometries (eccentric hypertrophy or normal geometry). Before propensity matching a parsimonious explanatory model was developed whereby variables found to be significantly associated with concentric geometry were identified. Confounding variables were balanced in the two groups with propensity analysis [20]. A propensity score was calculated for each patient from a logistic model that included 48 variables listed in Tables 1 and 2.
Patients with missing variables necessary for calculation of the propensity score were excluded from this analysis. No interaction terms were used. The C statistic for the propensity model was 0.768.
|
|
For both of the above propensity analyses, patients were 1:1 matched on propensity scores with greedy matching techniques [22]. Morbidity and mortality outcomes were compared between matched pairs with
2, Fisher's exact, and Wilcoxon rank-sum tests.
Logistic Regression
Logistic regression models were used to examine the relationship between LV geometry and mortality. In addition, further logistic regression analyses evaluated the relationship between RWT and LV mass on postoperative morbidity and mortality. Stepwise-selection logistic regression models were built from bootstrapping the data 1,000 times using the same 48 potential confounding variables as in the propensity analysis, but excluding the variable of interest, which differed in each analysis (LV geometry, RWT, or LV mass to height ratio). A bagging algorithm was used to summarize the results. Final logistic regression models for outcomes were built by using confounding variables that appeared in 50% of all models from the bootstrap procedure, then adding the variable of interest (LV geometry, RWT, or LV mass). Results were analyzed with SAS 8.2 software (SAS Institute Inc).
| Results |
|---|
|
|
|---|
|
|
Outcomes: Propensity-Matched Patients
Using the variables listed in Tables 1 and 2, 964 (28.0%) patients with concentric geometry (concentric LVH, n = 869; concentric remodeling, n = 95) were propensity matched to 964 (58.8%) nonconcentric geometry (eccentric LVH, n = 824; normal, n = 140) patients. Propensity matching resulted in a similar distribution of baseline and operative variables (Tables 1, 2). Mortality was significantly higher in patients with concentric geometry compared with those with nonconcentric geometry (38 [3.9%] versus 18 [1.9%]; p = 0.007). Cardiac morbidity (33 [3.4%] versus 17 [1.8%]; p = 0.022) and prolonged intubation (85 [8.8%] versus 58 [6.0%]; p = 0.019) were also higher in patients with concentric geometry. Renal, neurologic, infection, and overall morbidity did not differ significantly in patients with concentric and nonconcentric geometries (Table 5).
|
Outcomes: Logistic Regression
Because the propensity analysis matched only 38% of the patient population (964 patients in each group of the total 5,083 patients), logistic regression modeling was performed to adjust for confounding variables (listed in Tables 1 and 2) to compare outcomes in all patients. In addition, logistic regression techniques were able to compare each type of geometry individually. After adjustment for confounding variables, LV wall geometry was associated with an increased mortality risk (p = 0.009). Concentric hypertrophy increased risk of mortality compared with eccentric hypertrophy (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.21 to 3.20) and concentric remodeling increased risk of mortality compared with eccentric hypertrophy (OR, 3.23; 95% CI, 1.56 to 6.67). Risk of mortality was similar between patients with concentric hypertrophy and patients with concentric remodeling (OR, 0.62; 95% CI, 0.34 to 1.13). Eccentric hypertrophy versus normal (OR, 0.69; 95% CI, 0.24 to 1.99), concentric hypertrophy versus normal (OR, 1.36; 95% CI, 0.50 to 3.68), and concentric remodeling versus normal (OR, 2.21; 95% CI, 0.72 to 6.77) were not significantly different.
Relative wall thickness, but not LV mass, was associated with increased mortality, cardiac, renal, neurologic, and overall morbidity (Table 6).
|
| Comment |
|---|
|
|
|---|
Propensity modeling was used in our investigation to compare postoperative outcomes in patients by type of LV geometry. For the purpose of the propensity analysis, a dichotomous variable describing LV geometry was created such that patients were labeled as either concentric geometry or nonconcentric geometry. To form a dichotomous variable, patients with eccentric hypertrophy and normal geometry were combined into a single group. This technique allowed us to compare concentric geometry with all other geometries, and we found that patients with concentric geometries had an increased risk for early mortality after AVR. Further, logistic regression techniques were performed, which compared individual geometries and their association with adverse outcomes. The results from both analyses were consistent in that patients with concentric LVH and concentric remodeling were at increased risk for mortality compared with eccentric hypertrophy.
This analysis compared outcomes related to ventricular geometry, rather than type of aortic valve disease. The reasons for this comparison include the fact that other conditions (eg, other valvular disease, previous myocardial infarction, hypertension, and neurohormonal factors) in addition to type of aortic valvular disease contribute to ventricular remodeling and the development of concentric versus eccentric geometries. Certainly, more than 30% of patients with aortic stenosis have been found to have eccentric (rather than concentric) hypertrophy [23]. Thus, our objective was to evaluate the relationship between concentric LV geometry and outcomes after cardiac surgery rather than a comparison of aortic stenosis versus aortic insufficiency.
Outcomes were also compared between patients with concentric geometry and those with normal geometry. However, the number of patients with normal geometry was small—only 3.9% of patients with aortic valve disease have normal geometries. Our findings were consistent with our initial analysis: mortality, cardiac morbidity, and prolonged intubation in patients with concentric geometry were more than twice that of patients with normal geometry. However, because of the small sample size with normal geometry, this analysis lacked power to find a difference, and statistical significance was not achieved. It is also possible that some patients with normal geometry may have experienced acute aortic valvular dysfunction related to endocarditis or aortic dissection, before the development of chronic LV remodeling. These events may have increased risk for postoperative complications in patients with normal geometries and resulted in a smaller difference in outcomes. Because our investigation indexed LV mass to height, rather than to body surface area, obesity was less likely to underrecognize increased LV mass and falsely classify patients with LVH as normal LV mass [2, 18].
Our findings are consistent with other studies showing the association of LVH with adverse outcome after AVR surgery, including higher in-hospital mortality and morbidity [7–9]. Various descriptors of LVH severity have been used in other reports. As in our study, Orsinelli and associates [7] and Bech-Hanssen and coworkers [10] reported that patients with increased RWT and concentric hypertrophy were at increased risk of early postoperative mortality after AVR, although their investigations included only patients with aortic stenosis. In addition, Aurigemma and colleagues [24] reported that specific echocardiographic findings in patients, including more-pronounced hypertrophy, smaller cavities, and higher ejection fractions, were associated with increased postoperative mortality. These reports are in agreement with our findings that RWT predicts adverse outcome after AVR.
In contrast, other investigations used LV mass index, rather than RWT, to assess severity of LVH and evaluate its influence on outcomes after AVR [8, 9]. In contrast to our findings, Mehta and associates [8] reported that increased LV mass index was associated with adverse outcome after AVR with low cardiac output syndrome being the most common mode of death. Although Fuster and coworkers [9] reported that LV mass index was a predictor of early mortality and morbidity after AVR, considerably higher cutoff points were used to define increased LV mass (277 g/m2 in males, 251 g/m2 in females). Although cumulative mortality was increasingly higher for LV mass index values around 180 g/m2, patients with mild to moderate increase (cutoff points of 134 g/m2 in males, 110 g/m2 in females) in LV mass did not have an increase in mortality [9]. The cutoff points of increased LV mass in our investigation were at conventional levels [2, 18]. Thus, many of the patients that were classified as increased LV mass in our investigation would not have fit criteria for increased LV mass according to Fuster and colleagues [9]. Therefore, our results, which find that increased LV mass, conventionally defined, does not predict mortality after AVR do not contradict Fuster and coworkers [9]. Further study by Fuster and associates [25] found that severely increased LV mass index was associated with mortality only in patients with low LV ejection fraction. Consistent with this theory, Milavetz and colleagues [11] did not find that the degree of LVH, conventionally defined, influenced postoperative outcome after AVR.
An increased risk for early mortality in patients with concentric LV geometries undergoing AVR may be related to postoperative hemodynamic abnormalities, myocardial ischemia, and diastolic dysfunction. Patients with concentric LVH may be particularly susceptible to hemodynamic abnormalities in the immediate postoperative period as a result of the acute afterload reduction related to the removal of a stenotic aortic valve in addition to a stiff, noncompliant ventricle with impaired diastolic filling. Furthermore, an underfilled hypertrophied LV could be susceptible to dynamic LV outflow tract obstruction during systole [24]. Patients with concentric LVH are also at increased risk for preoperative myocardial ischemia as a consequence of structural alterations of the intramyocardial coronary vasculature, increased coronary resistance [26], coronary flow abnormalities [27], insufficient growth of coronary arteries relative to the degree of hypertrophied myocardial mass, and impaired subendocardial blood flow owing to increases in LV end-diastolic pressure. Further, myocardial oxygen demand is increased because of increased myocardial mass and higher wall tension, although myocardial efficiency is decreased [28] as increased interstitial fibrosis in the hypertrophied ventricle increases oxygen consumption, without contributing to LV minute work. Intraoperatively, patients with severe LVH are also at increased risk for suboptimal myocardial protection related to cardioplegic techniques [29], which may result in increased risk for development of myocardial dysfunction or arrhythmias. Diastolic dysfunction associated with concentric LVH [30] may also increase risk for adverse postoperative outcome. The presence of LVH amplifies the diastolic dysfunction that occurs with ischemia and reperfusion [31], which may further compromise cardiac output. These many factors may explain the increase in risk for adverse outcome in patients with concentric geometries after AVR.
Study Limitations
Because of its retrospective nature, the clinical data on the patients may be incomplete, and some determinants of outcome may not have been captured. Clinical care was not standardized; thus, selection bias and effects of unmeasured confounding variables cannot be excluded. Additionally, results from a single academic institution may not apply elsewhere because patient characteristics and care protocols will differ at least to some extent. However, a large, consecutive series from a single institution involving patients undergoing the same operation also reduces variability, thus making it easy to identify outcome patterns.
Conclusions
This investigation suggests that patients with concentric hypertrophy and concentric remodeling have worse outcomes than those with nonconcentric geometries. Increasing RWT, but not increasing LV mass, is associated with increased risk of early postoperative death. Further studies are required to address whether postoperative outcomes could be improved by AVR before a significant increase in RWT occurs.
| References |
|---|
|
|
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |